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The Quilmes were a native tribe who lived in the surroundings of Tucumán. In the 17th century, after repeated attempts by the Spanish invaders to control their lands, the Quilmes were defeated and were forced to settle in a restricted colony (reducción) near Buenos Aires, where the authorities could control them. The settlement was thus established in 1666 as Exaltación de la Santa Cruz de los Kilme. The 1,000 km (621 mi) journey from Tucumán was made on foot, causing hundreds of Quilmes to die in the process. The colony had been abandoned by 1810 and had become a ghost town. The land was divided in parcels and the town of Quilmes was established in 1818. During the first British invasion, the British arrived from Montevideo through Quilmes and went to Buenos Aires from there.

Quilmes proper consists of two main parts, east and west, which are divided by the tracks of the Metropolitano passenger train line. East Quilmes has several relatively wealthy areas and a large shopping district. As one travels east toward the Río de la Plata, neighborhoods become increasingly poor, and two large villas miseria (slums) are found close to the river. These areas often experience severe flooding.

The city also gives its name to Cerveza Quilmes beer company, as this is where it was first brewed in 1888 by the brewery started by Otto Bemberg; the establishment remains a leading employer in the city. Other significant manufacturers in Quilmes include textile maker La Bernalesa, glass maker Cattorini, construction materials maker Cerámica Quilmes, and climate control equipment maker Rheem.